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Neural development comprises the processes that
generate, shape, and reshape the nervous system, from the earliest
stages of embryogenesis to the final years of life. The study of
neural development aims to describe the cellular basis of brain development and to address
the underlying mechanisms. The field draws on both neuroscience and developmental biology to provide
insight into the cellular and molecular mechanisms by which complex
nervous
systems develop. Defects in neural development can lead to
cognitive, motor, and intellectual disability, as well as
neurological disorders such as autism, Rett syndrome, and mental
retardation.

Overview of brain
development

The brain emerges during embryonic development from the neural
tube, an early embryonic structure. The most anterior part of the
neural tube is called the telencephalon, which expands rapidly due
to cell proliferation, and eventually gives rise to the brain.
Gradually some of the cells stop dividing and differentiate into neurons and
glial cells, which are the main cellular
components of the brain. The newly generated neurons migrate to
different parts of the developing brain to self-organize into
different brain structures. Once the neurons have reached their
regional positions, they extend axons and dendrites, which allow
them to communicate with other neurons via synapses. Synaptic
communication between neurons leads to the establishment of
functional neural circuits that mediate sensory and motor
procesing, and underlie behavior.

Highly schematic flowchart of human brain development.

Aspects of neural
development

Some landmarks of neural development include the birth and differentiation of neurons from stem
cell precursors, the migration of immature neurons from
their birthplaces in the embryo to their final positions, outgrowth
of axons and dendrites from neurons, guidance of the
motile growth cone
through the embryo towards postsynaptic partners, the generation of
synapses between these axons
and their postsynaptic partners, and finally the lifelong changes
in synapses, which are thought to underlie learning and memory.

Typically, these neurodevelopmental processes can be broadly
divided into two classes: activity-independent mechanisms and
activity-dependent mechanisms. Activity-independent mechanisms are
generally believed to occur as hardwired processes determined by
genetic programs played out within individual neurons. These
include differentiation, migration
and axon
guidance to their initial target areas. These processes are
thought of as being independent of neural activity and sensory
experience. Once axons reach their
target areas, activity-dependent mechanisms come into play.
Although synapse formation is an activity-independent event,
modification of synapses and synapse elimination requires neural
activity.

Neural
induction

During early embyonic development the ectoderm becomes specified
to give rise to the epidermis (skin) and the neural plate. The
conversion of undifferentiated ectoderm to neuro-ectoderm requires
signals from the mesoderm. At the onset of gastrulation presumptive
mesodermal cells move through the dorsal blastopore lip and form a
layer in between the endoderm and the ectoderm. These mesodermal
cells that migrate along the dorsal midline give rise to a
structure called the notochord. Ectodermal cells overlying the
notochord develop into the neural plate in response to a signal to
a diffusible signal produced by the notochord. The remainder of the
ectoderm gives rise to the epidermis (skin). The ability of the
mesoderm to convert the overlying ectoderm into neural tissue is
called Neural Induction.

The neural plate folds outwards during the third week of
gestation to form the neural groove. Beginning in the future
neck region, the neural folds of this groove close to
create the neural
tube. The formation of the neural tube from the ectoderm is
called Neurulation. The anterior (front) part of
the neural tube is called the basal plate; the posterior (rear) part is
called the alar plate.
The hollow interior is called the neural canal. By the
end of the fourth week of gestation, the open ends of the neural
tube (the neuropores) close off.[1]

Identification of neural inducers

A transplanted blastopore lip can convert ectoderm into neural
tissue and is said to have an inductive effect. Neural Inducers are
molecules that can induce the expression of neural genes in
ectoderm explants without inducing mesodermal genes as well. Neural
induction is often studied in Xenopus embryos since they have a
simple body pattern and there are good markers to distinguish
between neural and non-neural tissue. Examples of Neural Inducers
are the molecules Noggin and Chordin.

When embryonic ectodermal cells are cultured at low density in
the absence of mesodermal cells) they undergo neural
differentiation (express neural genes), suggesting that neural
differentiation is the default fate of ectodermal cells. In explant
cultures (which allow direct cell-cell interactions) the same cells
differentiate into epidermis. This is due to the action of BMP4 (a
TGF-β family protein) that induces ectodermal cultures to
differentiate into epidermis. During neural induction, Noggin and
Chordin are produced by the dorsal mesoderm (notochord) and diffuse
into the overlying ectoderm to inhibit the activity of BMP4. This
inhibition of BMP4 causes the cells to differentiate into neural
cells.

The optical vesicle (which will eventually
become the optic nerve, retina and iris) forms at the basal plate
of the prosencephalon. The alar plate of the prosencephalon expands
to form the cerebral hemispheres (the telencephalon) whilst
its basal plate becomes the diencephalon. Finally, the optic vesicle
grows to form an optic outgrowth.

Patterning of the nervous
system

In chordates, dorsal ectoderm forms all neural tissue and the
nervous system. Patterning occurs due to specific environmental
conditions - different concentrations of signaling molecules

The ventral half of the neural plate is controlled by the notochord, which acts as
the 'organiser'. The dorsal half is controlled by the ectoderm plate which flanks
the neural plate on either side.

Ectoderm follows a default pathway to become neural tissue.
Evidence for this comes from single, cultured cells of ectoderm
which go on to form neural tissue. This is postulated to be because
of a lack of BMPs, which are blocked
by the organiser. The organiser may produce molecules such as follistatin, noggin and chordin which inhibit BMPs.

The ventral neural tube is patterned by Shh from the notochord, which
acts as the inducing tissue. The Shh inducer causes differentiation
of the floor plate. Shh-null tissue fails to generate all cell
types in the ventral tube, suggesting Shh is necessary for its
induction. The hypothesised mechanism suggests that Shh binds patched, relieving patched
inhibition of smoothend, leading to activation of gli transcription factors.

In this context Shh acts as a morphogen - it induces cell differentiation
dependent on its concentration. At low concentrations it forms
ventral interneurones, at higher concentrations it induced motor
neurone development, and at highest concentrations it induces floor
plate differentiation. Failure of Shh-modulated differentiation
causes haloprosencephaly.

The dorsal neural tube is patterned by BMPs from the epidermal
ectoderm flanking the neural plate. These induce sensory
interneurones by activating Sr/Thr kinases and altering SMAD transcription factor levels.

The hindbrain, for example, is patterned by Hox genes, which are
expressed in overlapping domains along the anteroposterior axis.
The 5' genes in this cluster and expressed most posteriorly. Hoxb-1
is expressed in rhombomere 4 and gives rise to the facial nerve. Without
this Hoxb-1 expression, a nerve which is similar to the trigeminal
nerve arises.

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Neuronal
migration

Neuronal migration is the method by which
neurons travel from their origin or birth place to their final
position in the brain. There are several ways they can do this,
e.g. by radial migration or tangential migration. (see time lapse sequences of
radial migration (also known as glial guidance) and somal
translocation.)[3]

Radial migration Neuronal precursor cells
proliferate in the ventricular zone of the developing neocortex. The first postmitotic cells to migrate
form the preplate which are destined to become Cajal-Retzius cells and subplate neurons. These cells do so by somal
translocation. Neurons migrating with this mode of locomotion are
bipolar and attachs the leading edge of the process to the pia. The soma is then
transported to the pial surface by nucleokinesis, a process by
which a microtubule "cage" around the nucleus
elongates and contracts in association with the centrosome to guide the
nucleus to its final destination.[4] Radial
glia, whose fibers serve as a scaffolding for migrating cells, can
itself divide[5]
or translocate to the cortical plate and differentiate either into
astrocytes or neurons.[6]
Somal translocation can occur at any time during development.[3]

Subsequent waves of neurons split the preplate by migrating
along radial glial
fibres to form the cortical plate. Each wave of migrating cells
travel past their predecessors forming layers in an inside-out
manner, meaning that the youngest neurons are the closest to the
surface.[7][8] It is
estimated that glial guided migration represents 90% of migrating
neurons in human and about 75% in rodents.[9]

Tangential migration Most interneurons migrate
tangentially through multiple modes of migration to reach their
appropriate location in the cortex. An example of tangential
migration is the movement of interneurons from the ganglionic
eminence to the cerebral cortex. One example of ongoing
tangential migration in a mature organism, observed in some
animals, is the rostral migratory stream
connecting subventricular zone and olfactory
bulb.

Others modes of migration There is also a
method of neuronal migration called multipolar
migration.[10][11] This
is seen in multipolar cells, which are abundantly present in the cortical
intermediate zone. They do not resemble the cells migrating by
locomotion or somal translocation. Instead these multipolar cells
express neuronal markers and extend multiple thin processes in
various directions independently of the radial glial fibers.[10]

Neurotrophic factors

The survival of neurons is regulated by survival factors, called
trophic factors. The neurotrophic hypothesis was formulated by
Victor Hamburger and Rita Levi
Montalcini based on studies of the developing nervous system.
Victor Hamburger discovered that implanting an extra limb in the
developing chick led to an increase in the number of spinal motor
neurons. Initially he thought that the extra limb was inducing
proliferation of motor neurons, but he and his colleagues later
showed that there was a great deal of motor neuron death during
normal development, and the extra limb prevented this cell death.
According to the neurotrophic hypothesis, growing axons compete for
limiting amounts of target-derived trophic factors and axons that
neurons that fail to receive insufficient trophic support die by
apoptosis. It is now clear that factors produced by a number of
sources contribute to neuronal survival.

Nerve Growth Factor (NGF): Rita Levi
Montalcini and Stanley Cohen purified the first trophic factor,
Nerve Growth Factor (NGF), for which they received the Nobel Prize.
There are three NGF-related trophic factors: BDNF, NT3, and NT4,
which regulate survival of various neuronal populations. The Trk
proteins act as receptors for NGF and related factors. Trk is a
receptor tyrosine kinase. Trk dimerization and phosphorylation
leads to activation of various intracellular signaling pathways
including the MAP kinase, Akt, and PKC pathways.

CNTF: Ciliary neurotrophic factor is another protein that acts
as a survival factor for motor neurons. CNTF acts via a receptor
complex that includes CNTFRα, GP130, and LIFRβ. Activation of the
receptor leads to phosphorylation and recruitment of the JAK
kinase, which in turn phosphorylates LIFRβ. LIFRβ acts as a docking
site for the STAT transcription factors. JAK kinase phosphorylates
STAT proteins, which dissociate from the receptor and translocate
to the nucleus to regulate gene expression.

GDNF: Glial derived neurotrophic factor is a member of the TGFb
family of proteins, and is a potent trophic factor for striatal
neurons. The functional receptor is a heterodimer, composed of type
1 and type 2 receptors. Activation of the type 1 receptor leads to
phosphorylation of Smad proteins, which translocate to the nucleus
to activate gene expression.

Synapse
formation

Neuromuscular junction Much of our
understanding of synapse formation comes from studies at the
neuromuscular junction. The transmitter at this synapse is
acetylcholine. The acetylcholine receptor (AchR) is present at the
surface of muscle cells before synapse formation. The arrival of
the nerve induces clustering of the receptors at the synapse.
McMahan and Sanes showed that the synaptogenic signal is
concentrated at the basal lamina. They also showed that the
synaptogenic signal is produced by the nerve, and they identified
the factor as Agrin. Agrin
induces clustering of AchRs on the muscle surface and synapse
formation is disrupted in agrin knockout mice. Agrin transuces the
signal via MuSK receptor to rapsyn. Fischbach and colleagues showed that
receptor subunits are selectively transcribed from nuclei next to
the synaptic site. This is mediated by neuregulins.

In the mature synapse each muscle fiber is innervated by one
motor neuron. However, during development many of the fibers are
innervated by multiple axons. Lichtman and colleagues have studied
the process of synapses elimination. This is an activity-dependent
event. Partial blockage of the receptor leads to retraction of
corresponding presynaptic terminals.

CNS synapses Agrin appears not to be a central
mediator of CNS synapse formation and there is active interest in
identifying signals that mediate CNS synaptogenesis. Neurons in
culture develop synapses that are similar to those that form in
vivo, suggesting that synaptogenic signals can function properly in
vitro. CNS synaptogenesis studies have focused mainly on
glutamatergic synapses. Imaging experiments show that dendrites are
highly dynamic during development and often initiate contact with
axons. This is followed by recruitment of postsynaptic proteins to
the site of contact. Stephen Smith and colleagues have shown that
contact initiated by dendritic filopodia can develop into
synapses.

Induction of synapse formation by glial factors: Barres and
colleagues made the observation that factors in glial conditioned
media induce synapse formation in retinal ganglion cell cultures.
Synapse formation in the CNS is correlated with astrocyte
differentiation suggesting that astrocytes might provide a
synaptogenic factor. The identity of the astrocytic factors is not
yet known.

Neuroligins and SynCAM as synaptogenic signals: Sudhof,
Serafini, Scheiffele and colleagues have shown that neuroligins and
SynCAM can act as factors that will induce presynaptic
differentiation. Neuroligins are concentrated at the postsynaptic
site and act via neurexins concentrated in the presynaptic axons.
SynCAM is a cell adhesion molecule that is present in both pre- and
post-synaptic membranes.

Synapse
elimination

Several motorneurones compete for each neuromuscular junction,
but only one survives till adulthood. Competition in vitro
has been shown to involve a limited neurotrophic substance that is
released, or that neural activity infers advantage to strong
post-synaptic connections by giving resistance to a toxin also
released upon nerve stimulation. In vivo it is suggested
that muscle fibres select the strongest neuron through a retrograde
signal.